本文關鍵詞： 肥胖 肥胖記憶 體重反彈 免疫系統(tǒng) CD4+T淋巴細胞 骨髓移植　出處：《南京大學》2017年博士論文　論文類型：學位論文

【摘要】：肥胖是體內脂肪過度積累的一種疾病,它會導致其他許多嚴重的病癥,例如心血管疾病,二型糖尿病和多種不同類型的癌癥。目前治療肥胖有多種方法,包括生活方式干預,控制能量攝入,增加運動量,各種減肥藥物的使用以及肥胖外科手術。但不幸的是,這些治療方法往往效果不好,原因是治療結束后甚至治療過程中病人就會出現(xiàn)體重反彈。體重反彈似乎難以避免,部分病人的體重甚至比治療前更重,這使得體重反彈成為肥胖治療中亟待解決的難題。本課題中,我們在小鼠模型中發(fā)現(xiàn)肥胖狀態(tài)會被身體記住,并且這種記憶會促使身體重新回到肥胖狀態(tài)。通過在C57BL/6J小鼠品系中建立增重-減肥-再增重的模型我們發(fā)現(xiàn),經(jīng)歷過肥胖和減肥的小鼠相比從未經(jīng)歷肥胖的小鼠而言,無論給予高脂飼料或者普通飼料,體重增加的速率都更快。不僅如此,肥胖記憶不是短期存在的,在小鼠中高脂誘導肥胖所產生的肥胖記憶能夠維持至少2個月的時間。這些現(xiàn)象說明肥胖會被身體長期記憶并導致機體即使瘦下來也會更快回到肥胖狀態(tài)。前人研究中提出過多種關于體重反彈的機制的假說,包括食欲增加,產熱下降和代謝水平降低。但我們發(fā)現(xiàn)這些猜測在肥胖記憶形成過程中并不成立。事實上,我們發(fā)現(xiàn)肥胖記憶形成時免疫系統(tǒng)被顯著激活,并且在免疫缺陷的Rag1敲除小鼠和免疫抑制劑處理的C57BL/6J小鼠中,肥胖記憶的現(xiàn)象消失了。有趣的是,通過把來自有肥胖記憶的小鼠的脾細胞注射入Rag1敲除小鼠體內,能夠重新建立肥胖記憶。這提示我們免疫系統(tǒng)的功能對于建立肥胖記憶是不可或缺的。不僅如此,通過移植有肥胖記憶小鼠的骨髓細胞可以向正常小鼠體內引入對肥胖的記憶。反之,用正常小鼠的骨髓細胞在肥胖記憶小鼠中重建免疫系統(tǒng)也能夠消除已有的記憶。進一步研究發(fā)現(xiàn),在肥胖記憶產生過程中,白色脂肪組織中CD4+T淋巴細胞數(shù)量顯著上升,尤其是促進炎癥發(fā)生的輔助T細胞Th1和Th17。在正常的C57BL/6J小鼠中剔除CD4+T淋巴細胞后則肥胖記憶被抑制。更驚人的是,單獨移植骨髓來源的CD4+ T淋巴細胞就足以向正常小鼠中引入肥胖記憶。這些結果說明CD4+T細胞在肥胖記憶的產生過程中起到至關重要的作用�？偠灾�,我們的研究結果揭示了肥胖可以被機體記憶這一新的理論,為反復出現(xiàn)并且無法避免的減肥后體重反彈現(xiàn)象提供了新的解釋。更重要的是,我們發(fā)現(xiàn)免疫系統(tǒng),特別是CD4+T淋巴細胞是產生和承載肥胖記憶的關鍵,為肥胖相關的研究以及關于肥胖和相關疾病的治療提供了新的見解。
[Abstract]:Obesity is a disease that accumulates too much fat in the body. It can lead to many other serious diseases, such as cardiovascular disease, type 2 diabetes, and many different types of cancer. There are many ways to treat obesity, including lifestyle interventions. Control of energy intake, increased exercise, use of various weight loss drugs, and obesity surgery. Unfortunately, these treatments tend to be ineffective. The reason is that at the end of the treatment and even during the course of treatment, the patient has a weight rebound. It seems inevitable that some patients' weight is even heavier than before the treatment. This makes weight rebound an urgent problem for obesity treatment. In this study, we found that obesity is remembered by the body in mouse models. And this memory can push the body back to obesity. By creating a weight-weight, weight-weight-reweight-gain model in the C57BL / 6J strain, we found that mice that had experienced obesity and lost weight were less likely to have experienced obesity than those who had never experienced obesity. Weight gain is faster whether given high-fat or regular diet. Not only that, obesity memory does not exist in the short term. Obese memory produced by hyperlipidemia in mice can last for at least two months. These phenomena suggest that obesity can be remembered by the body for a long time and lead to a faster return to obesity even if the body loses weight. Many hypotheses have been put forward about the mechanism of weight rebound. These include increased appetite, decreased heat production, and reduced metabolic levels. But we found that these assumptions don't hold true in obese memory formation. In fact, we found that the immune system was significantly activated during obese memory formation. And in the immunodeficient Rag1 knockout mice and the C57BL / 6J mice treated with immunosuppressants, the obese memory disappeared. Interestingly, by injecting spleen cells from the obese memory mice into the Rag1 knockout mice, The ability to recreate the memory of obesity suggests that the function of our immune system is essential for building memory of obesity. Not only that, By transplanting bone marrow cells from mice with obese memories, you can introduce the memory of obesity into normal mice. Using bone marrow cells of normal mice to reconstruct the immune system in obese memory mice could also eliminate the existing memory. Further studies showed that the number of CD4 T lymphocytes in white adipose tissue increased significantly during obese memory production. In particular, helper T cells Th1 and Th17. in normal C57BL / 6J mice, obese memory is suppressed after CD4 T lymphocytes are removed. Transplantation of CD4 T lymphocytes from bone marrow alone is sufficient to introduce obese memory into normal mice. These results suggest that CD4 T cells play a crucial role in the production of obese memory. Our findings reveal a new theory that obesity can be remembered by the body, providing a new explanation for repeated and unavoidable weight rebounding after weight loss. More importantly, we found the immune system. In particular, CD4 T lymphocytes are the key to the generation and carrying of obese memory, which provides new insights for the study of obesity and the treatment of obesity and related diseases.
【學位授予單位】：南京大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R589.2

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